How breast cancer stem cells resist chemotherapy

Working with human breast cancer cells and mice, researchers have identified a biochemical pathway that triggers the regrowth of breast cancer stem cells after chemotherapy.

The regrowth of cancer stem cells is responsible for the drug resistance that develops in many breast tumors and the reason that for many patients, the benefits of chemo are short-lived. Cancer recurrence after chemotherapy is frequently fatal.

Previous studies have shown that resistance to chemotherapy arises from the hardy nature of cancer stem cells, which are often found in the centers of tumors, where oxygen levels are quite low. Their survival is made possible through proteins known as hypoxia-inducible factors (HIFs), which turn on genes that help the cells survive in a low-oxygen environment.

The team found that the cancer cells that survived tended to have higher levels of a protein known as glutathione-S-transferase O1, or GSTO1. Experiments showed that HIFs controlled the production of GSTO1 in breast cancer cells when they were exposed to chemotherapy; if HIF activity was blocked in these lab-grown cells, GSTO1 was not produced.

Author notes that GSTO1 and related GST proteins are antioxidant enzymes, but GSTO1's role in chemotherapy resistance did not require its antioxidant activity. Instead, following exposure to chemotherapy, GSTO1 binds to a protein called the ryanodine receptor 1, or RYR1, that triggers the release of calcium, which causes a chain reaction that transforms ordinary breast cancer cells into cancer stem cells.

To more directly assess the role of GSTO1 and RYR1 in the breast tumor response to chemotherapy, the researchers injected human breast cancer cells into the mammary gland of mice and then treated the mice with carboplatin after tumors had formed. In addition to using normal breast cancer cells in the experiments, the team also used cancer cells that had been genetically engineered to lack either GSTO1 or RYR1. Loss of either GSTO1 or RYR1, the researchers report, decreased the number of cancer stem cells in the primary tumor, blocked metastasis of cancer cells from the primary tumor to the lungs, decreased the duration of chemotherapy required to induce remission and increased the duration of time after chemotherapy was stopped that the mice remained tumor-free.

Although the study showed that blocking the production of GSTO1 may improve the efficacy of chemotherapy drugs, such as carboplatin, GSTO1 is only one of many proteins that are produced under the control of HIFs in breast cancer cells that have been exposed to chemotherapy. The lab is working to develop drugs that can block the action of HIFs, with the hope that HIF inhibitors will make chemotherapy more effective.